Various compositions and methods for cleaning contact lenses have been described in the patent and scientific literature. Some of these methods have employed compositions containing surfactants or enzymes to facilitate the cleaning of lenses. The use of enzymes, particularly proteases, to clean contact lenses has been described in the patent and scientific literature. The first discussion of the use of proteolytic enzymes to clean contact lenses was in an article by Lo, et al. in the Journal of The American Optometric Association, volume 40, pages 1106-1109 (1969). Methods of removing protein deposits from contact lenses by means of proteolytic enzymes have been described in many publications since the initial article by Lo, et al., including U.S. Pat. No. 3,910,296 (Karageozian, et al.)
Numerous compositions and methods of use for disinfecting contact lenses have also been described. Those methods may be generally characterized as involving the use of heat and/or chemical agents. Representative chemical agents for this purpose include organic antimicrobials such as benzalkonium chloride and chlorhexidine, and inorganic antimicrobials such as hydrogen peroxide and peroxide-generating compounds. U.S. Pat. Nos. 4,407,791 and 4,525,346 (Stark) describe the use of polymeric quaternary ammonium compounds to disinfect contact lenses and to preserve contact lens care products. U.S. Pat. Nos. 4,758,595 and 4,836,986 (Ogunbiyi) describe the use of polymeric biguanides for the same purpose.
Various methods for cleaning and disinfecting contact lenses at the same time have been proposed. Such methods are described in U.S. Pat. Nos. 3,873,696 (Randeri, et al.) and 4,414,127 (Fu), for example. A representative method of simultaneously cleaning and disinfecting contact lenses involving the use of proteolytic enzymes to remove protein deposits and a chemical disinfectant (monomeric quaternary ammonium compounds) is described in Japanese Patent Publication 57-24526 (Boghosian, et al.). The combined use of a biguanide (i.e., chlorhexidine) and enzymes to simultaneously clean and disinfect contact lenses is described in Canadian Patent No. 1,150,907 (Ludwig). Methods involving the combined use of dissolved proteolytic enzymes to clean and heat to disinfect are described in U.S. Pat. No. 4,614,549 (Ogunbiyi). The combined use of proteolytic enzymes and polymeric biguanides or polymeric quaternary ammonium compounds is described in copending, and commonly assigned U.S. patent application Ser. No. 08/156,043 and in corresponding European Patent Application Publication No. 0 456 467 A2. Finally, a method involving the combined use of proteolytic enzymes in tablet form and a biguanide disinfectant is described in U.S. Pat. No. 5,356,555 (Huth).
Although the use of these enzymatic systems provides effective cleaning, a number of problems associated with their use exist. One problem is that residual amounts of the enzyme can bind to the contact lens. This binding can lead to less clarity of vision when using the lens. It can also lead to ocular irritation and immunogenicity, due to the eye's sensitization to the foreign protein. Consequently, the use of enzyme cleaning is generally limited to a once-per-week regimen. As a result, daily supplemental cleaning, which involves the rubbing of the lens with a surfactant, is necessary to clean the lens satisfactorily during the interim period between the weekly enzymatic cleanings. Thus, the contact lens user is burdened by the purchase of two separate cleaners and the employment of them separately in order to effectively clean his lenses. Therefore, although enzyme cleaning systems provide effective cleaning, they have not been fully exploited as a once-per-day regimen for the optimal cleaning and convenience they would otherwise provide. The modification of the enzyme to hinder its binding to the lens would reduce ocular irritation and immunogenicity, improve visual clarity, and therefore enable a more regular use of the enzyme for cleaning contact lenses.
Another problem in current enzyme cleaning which limits it to once-per-week usage is the cumbersome procedure of using tablets containing the enzyme. In order to use such compositions, a separate packet containing a tablet must be opened, the tablet must be placed in a separate vial containing a solution, and the tablet must be dissolved in order to release the enzyme into the solution. This practice is usually performed only once-per-week due to its cumbersome and tedious procedure. The use of enzyme tablets has been necessary, however, as liquid enzyme compositions formulated in the past have been inherently unstable. Therefore, the modification of the enzyme to improve its stability profile, especially for use in newly disclosed, improved liquid compositions, is of great interest.
The covalent linking of proteins with polyethylene glycol (PEG), to yield a polyoxyethylene-protein product, is disclosed by U.S. Pat. No. 4,179,337 (Davis et al.). A variety of publications and patents have described numerous types of PEG-modified proteins and methods of preparation. Davis et al., above, discloses PEG-modified or polypropylene glycol-modified, non-immunogenic polypeptides for use in the circulatory system of the human body. European Patent Application No. 0 584 876 A2 discloses low diol polyalkylene oxide biologically active proteinaceous substances, including a Subtilisin Carlsberg.
The particular covalent linkage is important for the utility desired. Several linkages have been reported, including succinates and carbamates (urethanes), which are disclosed in Cancer Biochemistry and Biophysics, volume 7, pages 175-186 (1984) and U.S. Pat. No. 5,234,903 (Nho et al.), respectively. Although the urethane linkage is purported to be an improvement in stability over the succinate linkage, both linkages are esters and are, therefore, susceptible to hydrolytic cleavage. The compounds of the present invention contain a stable ether or amide bond to facilitate a stable covalent linkage of a protease with an Al-PEG moiety.